Resistance and resilience to tau pathology in Alzheimer's disease: Effects of age, sex, and alleles.

Introduction: Neurofibrillary tangles (NFTs), a hallmark of tau pathology in Alzheimer's disease (AD), accumulate in the aging brain. However, some individuals remain cognitively intact despite high Braak (III-VI) stages, which characterize NFTs' accumulation.

Methods: We studied resistance and resilience to tau pathology by assessing Braak stages based on apolipoprotein E () alleles, sex, and age in a sample of 1932 cognitively intact individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP).

Results: Resistance, characterized by low (0-II) Braak stages, was observed in men and women younger than 85 years of age. Resilience, indicated by high (III-VI) Braak stages, increased significantly with age in both men and women for each allele. It became more pronounced, with the proportion of high Braak stages exceeding 50% at 85 years and older in women, irrespective of the allele.

Discussion: The identification of factors underlying resistance and resilience against AD-related pathologies is essential for promoting cognitively healthy aging.

Highlights: We investigated cognitive resistance and resilience to tau pathology in Alzheimer's disease (AD).This study included individuals who were not diagnosed with AD.Braak stages 0-II and III-VI were considered as a measure of resistance and resilience, respectively.Resistance was stronger at ages younger than 85 years in non-carriers of the apolipoprotein E () ε4 allele.Resilience increased with age for each allele independently of sex.At age 85 years and older, high resilience (>50%) was observed in women regardless of the allele.